As the worldwide epidemic of HIV-1 infection is primarily transmitted through sexual contact, the development of topical microbicides for the prevention of HIV infection is of major importance. To date, no effective anti-HIV microbicidal agent is available. Our group has developed chemokine (RANTES) analogues that provide sustained down-regulation of CCR5 expression and can block HIV propagation in vitro and prevent acquisition of HIV infection in the SCID hu-PBL-murine model. The specificity of the chemokine analogues for CCR5, the key co-receptor for acquisition of HIV-1 infection makes these products highly attractive for further development and early human trials. We propose that targeting the fusion step of HIV-1 replication with these chemokine analogues is a logical and novel approach to prevent HIV transmission and for microbicide development. In this project, we propose to initiate limited Phase I randomized double-blinded, placebo-controlled clinical trials of chemokine analogues (initially PSC-RANTES) first in HIV-uninfected couples in the U.S. and Uganda and then in HIV-infected couples. The trials will proceed as a sequence of studies of single agents beginning with a once daily dose for 7 days then proceeding through dose escalation and the advancing to twice daily dosing for up to 14 days in the HIV-uninfected participants. Based upon information gained from these trials, twice daily administration of a tolerated dose of the single agent will be studied in HIV-infected individuals. These studies will focus on the safety, tolerability, and acceptability of these products and provide critical formation about the effects of these compounds on human immune parameters. Additionally, we plan to evaluate the distribution of CCR5 promoter polymorphisms in study participants to provide background for evaluation of laboratory and clinical responses to the chemokine analogues. Lastly, we will determine whether the topical exposure to these analogues have an effect on vaginal HIV-1 isolates from HIV-infected women and will ask if viruses emerge as resistant to the compounds after 2 weeks of administration.